(258a) Modeling of Drug Delivery From PLGA Microspheres Using Reaction-Diffusion Equations with Hindered Diffusion

Controlled-release drug delivery systems provide alternatives to conventional medical drug therapy regimens which require frequent dosages due to short pharmaceutical in vivo half-life and poor oral bioavailability. Controlled-release systems have the potential to enhance control of drug concentrations, reduce side effects, and improve compliance as compared to conventional regimens.

Poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres are the controlled-release drug delivery system modeled in this work. Biodegradable PLGA microspheres have been extensively studied as drug delivery devices [1-3]. Modeling of the drug release from the devices must consider the interdependent phenomena that contribute to drug release. The microspheres encapsulate drug molecules dispersed throughout the polymer. The polymer undergoes autocatalytic hydrolysis, breaking the polymer bonds and generating smaller polymer chains with acidic end groups that catalyze further hydrolysis of the degradation products. Autocatalytic hydrolysis is more significant in the interior of large microspheres where the diffusion of degradation products is more limited [4-6]. Sufficiently small oligomers produced by the degradation are water-soluble and can diffuse out of the polymer microspheres through water-filled pores. The resulting polymer mass loss increases the pore volume in the microspheres. Encapsulated drug molecules diffuse through the aqueous pores in the polymer by hindered diffusion [7]. As the pore network in the microspheres evolves, the effective diffusivity of the drug increases.

A mathematical model has been developed for the simultaneous treatment of PLGA degradation and erosion and diffusive drug release with autocatalytic effects and nonconstant effective diffusivity of the drug [8-9]. A mechanistic reaction-diffusion model with pore evolution coupled to hydrolysis and related to the effective diffusivity through hindered diffusion theory is proposed. The unique contribution of the modeling work is that it combines autocatalytic PLGA degradation mechanisms [10-11] with hindered diffusion in aqueous pores [12] having variable pore sizes. The model performance for the case of drug release from microspheres of different sizes is presented to highlight the capability of the model for predicting size-dependent, autocatalytic effects on the polymer and the release of drug.

References

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